[O-062] Cantrixil Induces JNK-Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents In Vivo Recurrence.
Ayesha B Alvero, Eydis Lima, Natalia Sumi, Mary Pitruzello, David Brown, Andrew Heaton, Gil Mor. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA; CanTx, New Haven, CT, USA
INTRODUCTION: Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer (EOC). Chemoresistance is due to the presence of a group of cancer cells with stemness properties and high capacity for tumor repair. Current modalities are not able to target these cancer stem cells (CSC) thus there is a need to develop novel approaches. We created a library of super-benzopyran (SBP) analogues to generate compounds that can induce cell death in the chemoresistant CSC. We report the characterization of Cantrixil as a potent inducer of cell death in EOC stem cells and an effective maintenance treatment that prevents recurrence in an in vivo EOC model.
METHODS: A panel of SPB analogues were generated and activity was determined by testing against pure clones of CD44+/MyD88+ EOC stem cells and CD44-/MyD88- EOC cells using the IncucyteTM platform complemented by CelltoxTM dye labelling. Activation of cell death pathway was determined by Western blot. In vivo activity of the lead compound was tested using an intra-peritoneal (i.p) recurrent EOC xenograft model.
RESULTS: Of the 45 compounds screened, Cantrixil was the most potent in inducing cell death in all EOC stem cell clones tested (IC50 of 50 ng/ml). Cell death was associated with the activation of JNK pathway, loss of mitochondrial membrane potential, and caspase activation. In co-cultures of RFP+/CD44+/MyD88+ EOC stem cells and GFP+/CD44-/MyD88- EOC cells, co-treatment with Cantrixil and Cisplatin induced cell death in both EOC subtypes in contrast to treatment with Cisplatin alone, which induced cell death in only the GFP+/CD44-/MyD88- EOC cells. In vivo, Cantrixil significantly decreased i.p. tumor burden compared to vehicle control (p=0.03). In addition, using an in vivo recurrent EOC model, maintenance treatment with Cantrixil given after a Paclitaxel regimen prevented recurrent disease and significantly decreased metastatic tumor burden compared to maintenance with Paclitaxel (p = 0.002).
CONCLUSIONS: We described the characterization of a novel compound, Cantrixil, which exhibits significant in vitro and in vivo efficacy against chemoresistant EOC stem cells and is able to prevent in vivo recurrence. These results provide new opportunities for the development of novel therapeutic strategies that can improve patient survival.
Session: Concurrent Oral Session: Gynecologic Oncology (11:00 AM-12:30 PM)
Date/Time: Friday, March 27, 2015 - 11:45 am
Room: Continental 1-3
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